Project Summary/Abstract Hibernating mammals have evolved to be able to endure extreme stress, sub-zero temperatures and lack of food for up to 75% of the year. Understanding the genes and pathways involved in these adaptations would allow these mechanisms to be translated into human therapies. However, the key animal model for hibernation, the 13-lined ground squirrel, has yet to be fully developed. The lack of a centralized platform is one major obstacle preventing gene-based rational drug design from the protective effects of hibernation. In this proposal, we will build a multi-omics hibernation discovery platform for the 13-lined ground squirrel by integrating genomic, transcriptomic, proteomic and evolutionary analyses to generate novel drug targets. As part of this work, we will produce the first ATAC-seq study performed in a hibernating mammal, a key component of integrating genomic and transcriptomic data, as well as building networks to predict the function and regulation of predicted targets. We will additionally perform in-vitro? validation of the predicted drug targets from our integrated analyses. By developing a discovery platform for a model hibernator, the 13-lined ground squirrel, and demonstrating its utility, we will enable therapeutic discovery for diseases with large clinical needs like heart disease, stroke, Alzheimer?s, Type II Diabetes, and sarcopenia. This study is of interest to several NIH institutes (NIDDK, NHLBI, NINDS and NIAMS).